Cet article analyse le rôle des mutations somatiques et des agents environnementaux dans le développement tumoral

The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk

Balmain, Allan

Cancer is driven by genomic mutations in ‘cancer driver’ genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not sufficient for tumor development, thus prompting the question of how single mutant cells give [...]

Menée à l'aide d'un modèle murin de tumorigenèse associée à une colite, cette étude met en évidence un mécanisme par lequel des interactions entre le microbiote intestinal et des macrophages immatures induisent une réponse inflammatoire et facilitent le développement d'une tumeur

Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis

Yang, Yunben ; Li, Lili ; Xu, Chunjing ; Wang, Yunke ; Wang, Zhen ; Chen, Mengyao ; Jiang, Zhou ; Pan, Jun ; Yang, Chenghui ; Li, Xiaoqian ; Song, Kai ; Yan, Junfeng ; Xie, Wanglan ; Wu, Xianguo ; Chen, Zhigang ; Yuan, Ying ; Zheng, Shu ; Yan, Jun ; Huang, Jian ; Qiu, Fuming

Objective : Macrophages are among the most abundant cells in the colon tumour microenvironment, and there is a close relationship among monocytes, macrophages and the gut microbiota. Alterations in the gut microbiota are involved in tumour development, but the underlying mechanisms remain unclear. We aim to elucidate the temporal changes in macrophage subsets and functions, and how these dynamics are regulated by microbial cues in the initiation of colitis-associated cancer. Design : A mouse [...]

Menée sur des cellules épithéliales mammaires non tumorigènes, cette étude démontre que les espèces réactives de l'oxygène, générées par l'activation mécanique de la NADPH oxydase 2, prolongent la signalisation calcique des canaux TRPM8 et que cette signalisation est inhibée par l'oncogène KRAS

Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca2+ signals that are inhibited by oncogenic KRas

Pratt, Stephen J. P. ; Lee, Rachel M. ; Chang, Katarina T. ; Hernández-Ochoa, Erick O. ; Annis, David A. ; Ory, Eleanor C. ; Thompson, Keyata N. ; Bailey, Patrick C. ; Mathias, Trevor J. ; Ju, Julia A. ; Vitolo, Michele I. ; Schneider, Martin F. ; Stains, Joseph P. ; Ward, Christopher W. ; Martin, Stuart S.

In breast cancer, the chronically stiffening mechanical microenvironment promotes tumor growth/invasion. However, the molecular details and integration of cancer mechanotransduction signaling pathways are not well understood. We find that nontumorigenic breast epithelial cells are mechanically sensitive and respond to acute mechanical stimuli with the generation of ROS-stimulated calcium signaling in a microtubule-dependent manner. These results establish that epithelial cells conserve a [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel les plaquettes sanguines augmentent le degré d'agressivité des cellules gastriques cancéreuses en interagissant directement avec elles

Platelets enhance malignant behaviours of gastric cancer cells via direct contacts

Saito, Ryo ; Shoda, Katsutoshi ; Maruyama, Suguru ; Yamamoto, Atsushi ; Takiguchi, Koichi ; Furuya, Shinji ; Hosomura, Naohiro ; Akaike, Hidenori ; Kawaguchi, Yoshihiko ; Amemiya, Hidetake ; Kawaida, Hiromichi ; Sudo, Makoto ; Inoue, Shingo ; Kono, Hiroshi ; Suzuki-Inoue, Katsue ; Ichikawa, Daisuke

In this study, we aimed to analyse human cancer cell–platelet interactions in functional cell analyses and explore the molecular mechanisms behind tumour progression. Various functional analyses of gastric cancer (GC) cells were performed after direct/indirect co-incubation with platelets derived from GC patients. Further detailed expression and signalling analyses were performed after co-culture with direct and indirect GC cells–platelet contact. Malignant behaviours of cancer cells, such as [...]

Cet article passe en revue les mécanismes génétiques et épigénétiques impliqués dans le processus métastatique

Genomic control of metastasis

Patel, Saroor A. ; Rodrigues, Paulo ; Wesolowski, Ludovic ; Vanharanta, Sakari

Metastasis remains the leading cause of cancer-associated mortality, and a detailed understanding of the metastatic process could suggest new therapeutic avenues. However, how metastatic phenotypes arise at the genomic level has remained a major open question in cancer biology. Comparative genetic studies of primary and metastatic cancers have revealed a complex picture of metastatic evolution with diverse temporal patterns and trajectories to dissemination. Whole-genome amplification is [...]

Cet article analyse les mécanismes par lesquels l'hypersialylation peut favoriser la progression tumorale et le processus métastatique

Insights into the role of sialylation in cancer progression and metastasis

Dobie, Christopher ; Skropeta, Danielle

Upregulation of sialyltransferases—the enzymes responsible for the addition of sialic acid to growing glycoconjugate chains—and the resultant hypersialylation of up to 40–60% of tumour cell surfaces are established hallmarks of several cancers, including lung, breast, ovarian, pancreatic and prostate cancer. Hypersialylation promotes tumour metastasis by several routes, including enhancing immune evasion and tumour cell survival, and stimulating tumour invasion and migration. The critical role [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel la protéine mutante TP53, en interagissant avec le gène BRCA1, favorise le processus invasif des cellules cancéreuses

Mutant TP53 interacts with BCAR1 to contribute to cancer cell invasion

Guo, Alvin Kunyao ; Itahana, Yoko ; Seshachalam, Veerabrahma Pratap ; Chow, Hui Ying ; Ghosh, Sujoy ; Itahana, Koji

Background : Mutant TP53 interacts with other proteins to produce gain-of-function properties that contribute to cancer metastasis. However, the underlying mechanisms are still not fully understood. Methods : Using immunoprecipitation and proximity ligation assays, we evaluated breast cancer anti-estrogen resistance 1 (BCAR1) as a novel binding partner of TP53R273H, a TP53 mutant frequently found in human cancers. The biological functions of their binding were examined by the transwell invasion [...]

Menée à l'aide de lignées cellulaires, d'une xénogreffe sur un modèle murin et d'échantillons tumoraux issus de patients décédés d'un glioblastome, cette étude démontre que, durant la progression de la tumeur, la ferroptose induite par les neutrophiles favorise la nécrose des tissus tumoraux

Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression

Yee, Patricia P. ; Wei, Yiju ; Kim, Soo-Yeon ; Lu, Tong ; Chih, Stephen Y. ; Lawson, Cynthia ; Tang, Miaolu ; Liu, Zhijun ; Anderson, Benjamin ; Thamburaj, Krishnamoorthy ; Young, Megan M. ; Aregawi, Dawit G. ; Glantz, Michael J. ; Zacharia, Brad E. ; Specht, Charles S. ; Wang, Hong-Gang ; Li, Wei

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens [...]

Cet article analyse le rôle des mitochondries dans le processus métastatique

Roles of mitochondria in the hallmarks of metastasis

Scheid, Adam D. ; Beadnell, Thomas C. ; Welch, Danny R.

Although mitochondrial contributions to cancer have been recognised for approximately a century, given that mitochondrial DNA (mtDNA) is dwarfed by the size of the nuclear genome (nDNA), nuclear genetics has represented a focal point in cancer biology, often at the expense of mtDNA and mitochondria. However, genomic sequencing and advances in in vivo models underscore the importance of mtDNA and mitochondria in cancer and metastasis. In this review, we explore the roles of mitochondria in the [...]

Menée à l'aide d'échantillons sanguins et d'échantillons de moelle osseuse prélevés sur des patients atteints d'une leucémie myéloïde aiguë ou d'une autre néoplasie myéloïde, cette étude analyse, au moyen d'une technique de séquençage de l'ADN à l'échelle d'une seule cellule, le profil des mutations au cours de l'évolution clonale de la maladie

Single-cell mutation analysis of clonal evolution in myeloid malignancies

Miles, Linde A. ; Bowman, Robert L. ; Merlinsky, Tiffany R. ; Csete, Isabelle S. ; Ooi, Aik T. ; Durruthy-Durruthy, Robert ; Bowman, Michael ; Famulare, Christopher ; Patel, Minal A. ; Mendez, Pedro ; Ainali, Chrysanthi ; Demaree, Benjamin ; Delley, Cyrille L. ; Abate, Adam R. ; Manivannan, Manimozhi ; Sahu, Sombeet ; Goldberg, Aaron D. ; Bolton, Kelly L. ; Zehir, Ahmet ; Rampal, Raajit ; Carroll, Martin P. ; Meyer, Sara E. ; Viny, Aaron D. ; Levine, Ross L.

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later1–3. Although bulk sequencing can provide information about leukaemia biology [...]

Menée à l'aide d'échantillons sanguins, de tissus tumoraux et de tissus adjacents prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas et menée à l'aide d'une technique de cytométrie de masse, d'immunohistochimie multiplex et de séquençage de petits ARNs cytoplasmiques, cette étude analyse les caractéristiques immunitaires de la tumeur et de son environnement

Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer

Steele, Nina G. ; Carpenter, Eileen S. ; Kemp, Samantha B. ; Sirihorachai, Veerin R. ; The, Stephanie ; Delrosario, Lawrence ; Lazarus, Jenny ; Amir, El-ad David ; Gunchick, Valerie ; Espinoza, Carlos ; Bell, Samantha ; Harris, Lindsey ; Lima, Fatima ; Irizarry-Negron, Valerie ; Paglia, Daniel ; Macchia, Justin ; Chu, Angel Ka Yan ; Schofield, Heather ; Wamsteker, Erik-Jan ; Kwon, Richard ; Schulman, Allison ; Prabhu, Anoop ; Law, Ryan ; Sondhi, Arjun ; Yu, Jessica ; Patel, Arpan ; Donahue, Katelyn ; Nathan, Hari ; Cho, Clifford ; Anderson, Michelle A. ; Sahai, Vaibhav ; Lyssiotis, Costas A. ; Zou, Weiping ; Allen, Benjamin L. ; Rao, Arvind ; Crawford, Howard C. ; Bednar, Filip ; Frankel, Timothy L. ; Pasca di Magliano, Marina

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing and multiplex immunohistochemistry on patient tumors, matched blood and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed [...]

Cet article analyse les données concernant la prévalence, dans les cancers de la prostate, des altérations génétiques affectant les voies de réparation des dommages causés à l'ADN et passe en revue les implications cliniques de ces altérations

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

Lozano, Rebeca ; Castro, Elena ; Aragón, Isabel M. ; Cendon, Ylenia ; Cattrini, Carlo ; López-Casas, Pedro P. ; Olmos, David

Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum [...]

Cet article passe en revue les connaissances actuelles concernant les facteurs environnementaux et moléculaires du lymphome anaplasique à grandes cellules lié aux implants mammaires ainsi que les anomalies génétiques et chromosomiques intratumorales identifiées à ce jour

Biological and genetic landscape of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)

Rondón-Lagos, Milena ; Rangel, Nelson ; Camargo-Villalba, Gloria ; Forero-Castro, Maribel

Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon form of non-Hodgkin lymphoma (cancer of the immune system) that can develop around breast implants. Breast implants are among the most commonly used medical devices for cosmetic or reconstructive purposes. In the past few years, the number of women with breast implants diagnosed with anaplastic large cell lymphoma (ALCL) has increased, and several studies have suggested a direct association between breast [...]

Menée à partir du séquençage de l'ADN d'échantillons tumoraux et d'échantillons sanguins prélevés sur 2 enfants atteints d'un neuroblastome au niveau de chaque glande surrénale, cette étude analyse pour chaque enfant l'évolution génétique des deux tumeurs

Lineage-Independent Tumors in Bilateral Neuroblastoma

Coorens, Tim H. H. ; Farndon, Sarah J. ; Mitchell, Thomas J. ; Jain, Neha ; Lee, Sangjin ; Hubank, Michael ; Sebire, Neil ; Anderson, John ; Behjati, Sam

Childhood tumors that occur synchronously in different anatomical sites usually represent metastatic disease. However, such tumors can be independent neoplasms. We investigated whether cases of bilateral neuroblastoma represented independent tumors in two children with pathogenic germline mutations by genotyping somatic mutations shared between tumors and blood. Our results suggested that in both children, the lineages that had given rise to the tumors had segregated within the first cell [...]